Gum resin as a carrier for topical application of pharmacologically active agents

ABSTRACT

The invention provides a biological dressing for treatment of a dermatological disease comprised of a gum resin, a topically acceptable volatile solvent, and a pharmacologically active agent. The gum resin is present in a suitable amount that the composition, when the solvent evaporates, will dry to form a solid coating that sticks to the skin or mucosal membrane to which the composition is applied and maintain the pharmacologically active agent over a sustained period of time in contact with sites on the skin or mucosal membranes exhibiting symptoms of the disease. Methods are provided for treating symptoms of dermatological diseases with such a pharmacological composition. Biological dressings including tincture of benzoin and clotrimazole are shown to be efficacious for the long-term amelioration of symptoms of athlete&#39;s foot.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of priority to provisionalapplication U.S. Ser. No. 60/299,377 filed Jun. 18, 2001, whichdisclosure is hereby incorporated by reference.

INTRODUCTION

[0002] 1. Technical Field

[0003] The invention relates to gum resin based biological dressingsthat adhere to the skin and contain one or more pharmacologically activeagents for the treatment of symptoms relating to dermatological diseasesand those affecting mucous membranes. The invention is exemplified bybiological dressings comprising tincture of benzoin and clotrimazole forthe treatment of athlete's foot.

[0004] 2. Background

[0005] For many forms of dermatological conditions, the powders, sprays,solutions, lotions and creams available over-the-counter lackeffectiveness. The reason for this varies, from poor delivery of themedication to the source or cause of the condition, to loss of themedication through abrasion from normal activity of the patient, toabsorption of medications applied to the skin by the patient's socks orclothes. For these various reasons, currently available commercialmedications are prone to come off easily once applied to the affectedarea, and consequently much of the medication is wasted, either throughover application in an attempt to anticipate the problem, or in medicinequickly being dispersed away from the site. The medications for theseconditions typically require at least 2 to 4 weeks of continuoustreatment, and thus often fail due to this poor delivery.

[0006] A further problem with the use of existent medications is thelack of compliance by patients. Due to the mess and difficulty of use,patients will often use these over the counter medications only untiltheir symptoms abate and then they will stop the medication, before therecommended course of treatment is completed, and hence often before theinfection has truly cleared. Though momentarily abated, the infectionthen begins to take hold again, and in a matter of days or weeks a fullblown infection occurs again. In many cases the patient will repeatusing the over the counter medication until the symptoms clear, andagain stop the medication with the first sign of abatement, with thewhole cycle repeating.

[0007] Hence, there is a need for a clean and inexpensivevehicle/carrier of topically applied medications that increases theconvenience and effectiveness of the treatment and decreases thenecessary time for the treatment. It is preferably associated with lesswaste and lower cost and ultimately leads to improved treatment ofpatient symptoms and increased patient satisfaction.

[0008] 3. Description Of Related Art

[0009] In medicine, tincture of benzoin and mastic gum (Mastisol) havebeen employed to form a sticky coating on skin prior to the placement ofadhesive preparations. Tincture of benzoin has also been used to form abiologic dressing over superficial cutaneous wounds as well as apthousulcers (canker sores). However, the general use of gum resins, such asmastic gum and benzoin gum, as semi-permanently applied carriers forincreasing the efficacy and usefulness of topological of pharmacologicalagents has not been disclosed.

[0010] A tincture of benzoin has been used with podophyllin resin(10-25%) in the treatment of genital warts. It is considered by many tobe cumbersome and inconvenient (see U.S. Pat. Nos. 5,063,065 and5,167,649). Unfortunately, podophyllin resin is toxic, and even whenapplied in a tincture of benzoin, this agent must be removed by rigorouswashing 1 to 6 hours post-application. Due to the problems associatedwith using podophyllin resin in tincture of benzoin, other carriers havebeen sought. As an example, in the treatment of genital warts, Goh, etal. (Singapore Med J (1998) 39:17-19) reports that podophyllin preparedin 0.25% ethanol can be self-applied and is as efficacious aspodophyllin prepared in tincture of benzoin and applied in the clinic.Use of tincture of benzoin as a biological bandage with compounds thatit is desirable to have in long contact with the skin has not beenreported.

SUMMARY OF THE INVENTION

[0011] Compositions and methods are provided for increasing theeffectiveness of treatment of dermatological disorders on the skin or amucous membrane of a mammal by using a gum resin as a carrier for apharmacologically active agent. The pharmacological compositions arecomprised of a gum resin, at least one topically acceptablepharmacologically active agent for treatment of a dermatologicaldisorder other than the gum resin, wherein the active agent is non-toxicto the mammal being treated when left in contact with the lesion ofinterest for at least 6 hours, and a topically acceptable volatilesolvent. The compositions optionally can include a penetration enhancer.The methods of treating symptoms of a dermatological disorder includethe steps of contacting affected sites on the skin of a patient in needthereof with the pharmacological composition comprised of a gum resin, apharmacological agent or agents, and an evaporative solvent, andallowing it to dry to form a biological dressing. The biologicaldressing comprises a sticky film of gum resin and a pharmacologicallyactive agent left on the skin or mucous membrane after the volatilesolvent has evaporated. The dressing forms a hydrophobic, protectivefilm that provides sustained release of the pharmacologically activeagent at the site of application. The invention finds use in thetreatment of dermatological disorders such as infection, inflammation,and hyperproliferation of epidermal cells.

DETAILED DESCRIPTION OF THE INVENTION

[0012] Compositions and methods are provided for the convenient andeffective treatment of at least one symptom of a dermatologicaldisorders in a mammal, particularly a human, in need thereof, with abiological dressing. By “biological dressing” or “biologic dressing” or“biologic bandage” is intended a non-occlusive but adherentpharmacological composition that is formed by drying on the skin apharmacologic composition comprised of a gum resin, such as benzoin ormastic gum, a pharmacologically active agent and topically acceptablevolatile solvent, such as ethanol. The biologic dressing forms aprotective coating at the site(s) on the skin or mucosal membraneexhibiting symptoms of the disorder and also acts as a reservoir for thepharmacolocally active agent(s) to provide sustained delivery of anappropriate medication or combination of medications to the site. Theskin disorder symptoms to be treated include skin and mucosal membranelesions, inflammation, itching, scaling and pain. The disorders includeviral, fungal and bacterial infections, inflammatory conditions, andhyperproliferative disorders. The pharmacological agent(s) can includetopically active agents that can be used to ameliorate skin disordersymptoms, including antimicrobial and antiviral agents,anti-inflammatory agents, analgesics and anesthetics. As desired, theeffectiveness of the pharmacological agent(s) optionally can beincreased by including skin a penetration enhancer in the pharmacologiccomposition. The biological bandage is easily removed using a solventsuch as ethanol. Since the coating that contains the medication stays inplace until such deliberate removal, the effectiveness of the treatmentis increased since the skin is exposed to the active ingredient for alonger period of time. This also allows for a decreased treatment time,and, ultimately, improved treatment of symptoms and increased patientsatisfaction. Thus, compositions of the invention can be used to improvedelivery of medications that are soluble in organic solvents such asalcohols that are typically applied topically for the treatmentdermatologic disorders.

[0013] The advantages of the subject invention include a morespecifically directed application of medications to sites affected by askin disorder, and extended retention on the skin of the medicationbecause the film is resistant to water and abrasion by clothing.Additionally, the vehicle is relatively inexpensive, is pleasantsmelling, and the bandage can be conveniently and easily removed, forexample with alcohol, when desired. Many dermatological conditions areexacerbated by moisture so the water repellent qualities of the dressingalso protect the skin from further damage. The biological dressings aredesigned to be directly applied to a lesion needing treatment, and leftin place for an extended period of time, without requiring conventionaladhesive bandages. It is intended that the dressing need only be washedfrom the lesion for purposes of convenience and cleanliness. Thebiological dressings of the subject invention are cleaner and easier toapply than conventional dressings and existing medications, have lesswaste and are more economical, allowing for more efficient, efficaciousand palatable relief of symptoms or recovery from the skin disorderbeing treated. A further advantage of the subject invention is thatvarious of the gum resins that find use, including benzoin and mastisol,are already approved for human use and have been tested and found to besafe for topical application on non-human mammals.

[0014] The biological dressings are prepared by drying on the skin, apharmacological composition comprising an agent that can be used toameliorate the symptoms of a dermatological disease and a gum residuedissolved in a volatile solvent. Generally, the pharmacologicalcomposition is prepared as a sticky slurry or solution that can beapplied to a site on the skin or a mucosal membrane. The consistency ofthe pharmacological composition can be varied by adjusting the ratio ofsolvent to gum residue in the composition to achieve the desiredconsistency for application to a particular site. For areas whereevaporation of solvent may be slower, for example, application tolesions on a mucosal membrane such as the gums, it may be desirable toprepare the composition as a paste and to use a more volatile solvent,whereas for application to hard to reach areas, such as between thetoes, it may be desirable to prepare a less viscous composition that canbe applied thinly to the affected areas. However, for treatment of moresevere lesions in non-visable areas, due to an athlete's foot infectionfor example, application of a more viscous preparation may be preferred.The relative proportions of the gum resin carrier, the pharmacologicallyactive agent or agents and the evaporative solvent in the preferredcomposition can vary widely, and will depend upon the specific intendeduse of the biological dressing. Precise preferred ratios will depend tosome extent on the rate of release of the pharmacologically active agentfrom the film, the desired stickiness of the residual film, and the areaof application. For example, if the intended application is to anaffected area on the face, the preferred composition would have a lowerproportion of gum resin, to allow for a more thinly applied and lessvisible and less sticky medical dressing. Generally, the pharmacologicalcompositions of the subject invention will have at least about 10% gumresin, more likely about 20%, 30% or 40% gum resin, as much as 50% or60% gum resin.

[0015] The stickiness of the biological dressings is provided by the useof a gum resin, generally, naturally occurring gum resins, such as thosethat are harvested from trees are used, although gum resins also may beprepared by synthetic means (see for example, U.S. Pat. Nos. 5,644,049,5,429,590 and 4,307,717). Preferred gum resins include benzoin resinousexudate harvested from Styracaceae trees, including Benzoin Siam fromStyrax tonkinesis and Benzoin Sumatra from Styrax benzoin. Tincture ofbenzoin and benzoin compound tincture is readily available throughnumerous commercial sources, including many drug stores and suppliers ofsurgical goods. Another resinous tree exudate that is preferred and iscommonly used in the medical arts for enhancing the adherence ofsurgical bandages, is mastic gum, which is harvested from Pistacialentiscus. A tincture of mastic gum (Mastisol) is produced by FerndaleLaboratories in Ferndale, Mich. and is also available through suppliersof surgical goods. Other gum resins that can be used include the gumresin exudate from Burserceae trees, including Boswellia serrata (alsoknown as Boswellin), Boswellia dalzielli, Boswellia carteri (gumolibanum) and Canarium luzonicum or Canarium commune (Elemi gum orresin). Additional resinous exudates contemplated from other treespecies include Eucalyptus species (Eucalyptus globulus) and Myrtaceae“Tea-tree” species (Melaleuca alternifolia, Leptospermum scoparium, andKunzea ericoides). Many naturally occurring gum resins themselves havepharmacological properties, and their topical application may causeirritation in certain patients or exacerbate certain conditions. Prudentchoice of gum resin to be used in preparing a particular biologicaldressing will take into consideration the dermatological disorder to betreated and the sensitivities of a particular patient's skin.

[0016] A desirable feature of the subject compositions is that they dryto form a sticky, adherent and protective film or biological bandageover a dermatologic lesion. To effect this attribute, thepharmacological composition is prepared with a volatile solvent thatevaporates to leave a hydrophobic coating comprised of the gum resin andthe pharmacological agent on the skin. Volatile solvents for use in thesubject compositions include alcohols such as methanol, ethanol,propanol, and isopropanol, and ketones, such as acetone. Otherevaporative compounds may also find use, so long as they are compatiblewith other components of the pharmacological composition and topicallyacceptable to the majority of patients. The gum resin of choice isdiluted in the volatile solvent such that the concentration of solventcomprises at least about 40% or 50% (v/v or v/w), more commonly at leastabout 60%, 70% or 80%, or as much as about 90% of the total composition.A particularly preferred composition is a tincture of benzoin, which iscomprised of benzoin in about 60%, 70%, 80% or 90% ethanol.

[0017] The pharmacological agent or agents included in thepharmacological compositions will depend upon the dermatologicaldisorder being treated. To allow for extended contact of the biologicaldressing with the lesion under treatment, pharmacological agents chosenshould be efficacious without being locally or systemically toxic orcaustic to the mammal to which the medicated dressing is administered. Abiological dressing of the subject invention is intended to remain atthe site of application for at least 6 hours, more often as long as 8,10 or 12 hours, sometimes as long as 16, 18 or 20 hours, and for certaintreatments, as long as 24, 36 or 72 hours or even longer prior toremoval. The time of treatment desired is based at least in part uponthe nature of the condition to be treated and the pharmacologicalagent(s) that are being used. In general, the pharmacologicalcompositions are formulated so that the concentration of thepharmacological agent(s) that is in the biological bandage approximatesthe concentration of agent that is used in existing topicalformulations. However, because the adherent properties of a gumresin-based biological dressing allow for extended and continuousexposure of a skin lesion to drug, reduced concentration formulationsare possible and even preferred. The amount to be used can therefore beadjusted as appropriate. Generally, the amount used will be within therange of ±25% of the indicated concentration, preferably within ±10% ofthe indicated concentrations. In the following paragraphs, thepercentages appearing in parenthesis after the name of a particularagent represent the concentration(s) of agent that is(are) used inexisting topical formulations.

[0018] The subject biological dressings find particular use in treatingnumerous dermatological disorders, including superficial infections(fungal, bacterial, viral and parasitic), and inflammatory skindisorders. Additional uses include sustained delivery of pharmacologicalagents for hair growth stimulation and hair growth retardation, skinpigmenting and pigmentation removal agents, sunscreens, insectrepellents, anti-anginal, anti-perspirant and anti-nausea agents.

[0019] Superficial fungal infections treatable by the subjectcompositions include those caused by mold-like fungi (dermatophytes ortinea) or yeast-like fungi (Candida) that are confined to the stratumcorneum or squamous mucosa. Particularly considered is the treatment oftinea infections including athlete's foot (tinea pedis), ringworm (tineacapitis), jock itch (tinea cruris), tinea corporis, tinea manuum andtinea versicolor. Other dermatological fungal infections treatable withthe described biological dressings include Candida, Epidermophyton,Microsporum, Trichophyton and Pityrosporum infections. Compositions forthe treatment of superficial fungal infections will include at least oneanti-fungal pharmaceutical agent. Anti-fungal agents for use in abiological dressing composition include those well-known in the art,such as clotrimazole (0.5%, 1.0%, 2.0%), ketoconazole ((1%, 2%),econazole (1%), miconazole (2%), terconazole (0.4%), butoconazole (2%),oxiconazole (1%), sulconazole (1%), ciclopirox olamine (1%), haloprogin(1%), tolnaftate (1%), amphotericin B (3%), butenafine (1.0%),terbinafine (1.0%), naftifine, nystatin and griseofulvin. Referencesthat can be consulted to aid in the selection of an appropriatepharmacological agent include Goodman and Gilman's “The PharmacologicalBasis of Therapeutics”, 9^(th) Edition, 1996, Pergamon Press, New York,and the lastest edition of the Physician's Desk Reference published byMedical Economics Company, Montvale, N.J.).

[0020] Secondary bacterial infections that may arise in conjunction withthe primary fungal infection can be treated simultaneously orprophylactically by additionally including a topically compatibleantibiotic pharmacological agent in the biological dressing. Antibioticmedications known in the art that will find use in preparation of thesubject compositions include clindamycin (1%), erythromycin (1.5%,2.0%), tetracycline (3%), mupirocin (2.0%), gentamycin (0.1%),metronidizole (0.75%, 1%), bacitracin, neomycin and polymyxin B. Acomposition with a combination of antibiotics against different strainsof bacteria will be preferred for certain treatments. A steroidalpharmacological agent, such as betamethasone (0.025%, 0.05%, 0.1%), in abiological dressing intended to treat a fungal infection canadditionally be included to enhance the retraction of the lesion.

[0021] Biological dressings having an antibiotic medication as theprimary pharmacological agent can be prepared to treat other skindisorders for which such medications are traditionally used, includingas impetigo contagiosa, acne vulgaris, other superficial skin infectionsof unknown etiology, and post-operative superficial skin infections(e.g., infections that occur around the insertion of a catheter). Woundhealing can be aided and colonization of wounds (i.e. isolated areaswith first-degree burns) can be inhibited by application of a biologicaldressing comprising silver sulfadiazine (1%). The particular antibioticselected to include in the biologic dressing will of course depend onthe agents to which the strain of bacteria causing the infection issensitive, and the specific needs of the patient.

[0022] A gum resin dressing can also be prepared for the treatment ofsuperficial parasitic infections, such as scabies, nits and lice(including head lice and crab lice). For treating such infections,pharmacological compositions comprising miticides or pediculocides suchas crotamiton (10%) or permethrin (5%), lindane (1%), malathion (0.003%,0.06%, 0.5%), benzyl benzoate (26% to 30%), thiabendazole andpyrethrins.

[0023] For treating pain associated with arthritis, joint inflammationand muscle pain a gum resin dressing can be prepared containing one ormore active ingredients such as menthol (10%), methyl salicylate (10%)and capsaicin (0.01%-10%) or a corticosteriod (see below for appropriatecompounds and dosages). The biological dressing compositions also finduse in the treatment of dermatological inflammatory disorders, whereinthe primary pharmacological agent included is a corticosteroid.Particularly contemplated is the treatment of corticosteroid-responsiveinflammatory conditions, such as atopic dermatitis or eczema, seborrheicdermatitis, some forms of psoriasis, apthous ulcers (canker sores),superficial skin lesions due to contact with poisonous plants such aspoison oak or poison ivy, insect bites, and other skin rashes of unknownetiology. Steroidal agents of all different grades (1-7) that are knownin the art can be included in a biological dressing preparation, such asbetamethasone (0.025%, 0.05%, 0.1%), clobetasol (0.05%), diflorasone(0.05%), amcinonide (0.1%), desoximetasone (0.05%, 0.25%), fluocinonide(0.05%), halsinonide (0.1%), triamcinolone (0.025%, 0.1%, 0.5%),hydrocortisone (0.1%, 0.2%, 0.5%, 1.0%, 2.5%), flurandrenolide (0.05%),alclometasone (0.05%), fluocinolone (0.01%, 0.025%, 0.2%), desonide(0.05%), desamethasone (0.1%) and methylprednisolone (1.0%),clocortolone (0.1%), fluticasone (0.05%, 0.005%), mometasone (0.1%),prednicarbate (0.1%), amcinonide (0.1%), and halobetasole (0.05%). Theparticular corticosteriodal agent selected will depend on the patientand the dermatological disorder being treated.

[0024] For the treatment of certain skin disorders, non-steroidal drugsmay be appropriate. As an example, a biological dressing comprisingsalicylic acid (2.5%, 5%, 10%, 20%, 40%, 60%) would be suitable for thetreatment of acne, psoriasis, warts, and other hyperkeratotoicdisorders. Cantharidin (0.7%), imiquimod (5%), and podofilox (0.5%) areother examples of pharmacological agents for use in a biologicaldressing prepared for the treatment of warts, including genital warts.Other pharmacological agents suitable for the treatment of acne includetretinoin (0.025%, 0.05%, 0.1%, 0.2%), isotretinoin, adapaline (0.1%),azelaic acid (20%), clindamycin, erythromycin, tetracycline, benzoylperoxide (2.5%, 5%, 10%), and sulfacetamide (10%). A gum resincomposition comprising metronidazole (0.75%) finds use in the treatmentof rosacea. Biological dressings comprising anthralin (0.1%, 0.2%,0.25%, 0.4% and 0.5%), calcipotriene (0.005%) and/or tazarotene find usein the treatment of psoriasis.

[0025] For certain inflammatory dermatological conditions, it may bedesirable to include one or more anti-histamine compounds with asteroidal compound in the biological dressing compositions to aid inrelieving itching that is often associated with inflammatory lesions.Histamine H₁ and H₂ receptor blockers known in the art are of use in thepreparation of biologic dressings for treating certain inflammatory skinconditions include the H₁ blockers astemizole and terfenadine and the H₂blocker cimetidine.

[0026] Dermatological conditions which can be treated withphamacological composition in which an anti-histamine is the primaryagent include urticaria, and itching associated with lymphoproliferativediseases such as polycythemia rubra vera and Hodgkin's disease.Oftentimes best results are achieved when using both an H₁ and an H₂blocker. Additionally, a medicated gum resin dressing comprising theanti-pruritic doxepin (5%) finds use in relieving the itching inpatients with certain types of eczema. Topical doxepin appears to workby preventing the effects of histamine.

[0027] A gum resin carrier also finds use in the treatment ofsuperficial dematological viral infections, whenever topical anti-viralmedications would be indicated. Particularly considered is theadministration of acyclovir (5%) for the treatment of viral infectionscaused by herpes (type 1 and type 2) simplex viruses, but a biologicaldressing can also be applied to superficial skin infections caused bypapillomavirus (for example, common and genital warts). Other examplesof anti-viral agents for use in a biological dressing includegancyclovir, penciclovir (1%), vidarabine (3%), idoxuridine (0.5%) andtrifluridine.

[0028] A biological dressing also finds use in providing relief frompain associated with the lesions caused by some dermatologicaldisorders. Particularly considered is treatment of the dermal pain thatcan be associated with varicella-zoster virus (shingles, chicken pox)with a topically compatible local anesthetic. A preferredpharmacological agent for use in a gum resin-based dressing prepared fortreating pain associated with dermatological disorders is lidocaine(0.5%, 1%, 2%, 5%, 10%, 20%, 25%, see U.S. Pat. Nos. 5,709,869,5,601,838, 5,589,180 and 5,411,738). Other local anesthetics chemicallyand/or pharmacologically related to lidocaine, or lidocainehydrochloride, include bupivacaine hydrochloride (0.25%, 0.5%, 0.75%,1.5%), etidocaine hydrochloride (1.0%, 1.5%, 3.0%), mepivacainehydrochloride (1.0%, 1.5%, 2.0%, 3.0%, 5.0%), prilocaine hydrochloride(4.0%, 8.0%), and tetracaine hydrochloride (0.5%, 1.0%, 2.0%). Otherpreferred local anesthetics are those with low solubility in water, andwhich are particularly suited for sustained local anesthetic action whentopically applied. Examples of local anesthetics with low solubility inwater include benzocaine and the hydroiodide salt of tetracaine.Additional local anesthetics used in treating mucous membranes and theskin include dibucaine, dyclonine hydrochloride (0.5%, 1.0%), andpramoxine hydrochloride (1.0%), Another example of a pharmacologicalagent used topically to relieve dermatological pain includes capsaicin(0.025%).

[0029] Gum resin compositions containing synthetic hormones find use inthe treatment of indications associated with abnormal hormone productionas well as contraception. For example, a gum resin compositioncontaining transdermal testosterone, generally about 2.5-5.0 mg perapplication, or equivalent other androgenic compound(s) in anappropriate amount can be used to treat young males with congenital oracquired primary hypogonadism, or congenital or acquiredhypogonadotropic hypogonadism and other similar disorders. In women, agum resin composition containing estradiol (an active form of estrogen)or other equivalent estrogenic compound(s) in an appriopriate amount,can be used to treat the indications and symptoms associated withatrophic vaginitis, atrophic dystrophy of the vulva, menopausalsymptoms, female hypogonadism, ovariectomy, primary ovarian failure,non-steroid dependent inoperable breast cancer and vasomotor symptomsassociated with menopause and prevention of post-menopasualosteoporosis. A gum resin composition containing an estrogenic compound,such as for example estradiol in an amount sufficient for the treatmentof such indications is used.

[0030] A composition containing norethindrone (progestin) can be used toprevent pregnancy by inhibiting ovulation and thickening the mucosa ofthe cervix. In addition, a gum resin composition containing a progestincompound such as norethindrone (0.14-0.25 mg per application) can beused for treating abnormal menstrual disorders such as amenorrhea,abnormal uterine bleeding and endometriosis, applications generally willbe to the skin. The site of application of the gum resin compositionwill vary depending upon the intended use. Generally the site ofapplication will be to the skin at a location that will provide forabsorption into the blood stream. Particularly in the case of treatmentsrelating to the female genitalia, application can be intravaginally

[0031] Gum resin compositions are also suitable for sustained deliveryof pharmacological agents use for hair growth retardation andstimulation. For treatments intending to stimulate hair growth,compositions comprising minoxidil (1%, 2%, 5%) are prepared. For othertopical formulations that can be used with the gum resins, see U.S. Pat.No. 6,184,249. For treatment intending to retard hair growthcompositions comprising eflornithine hydrochloride (13.9%) are prepared.

[0032] A gum resin vehicle additionally finds use in preparingprotective compositions comprising sun protecting, ultravioletabsorptive agents. Sunscreens for use in a gum resin-based dressinginclude aminobenzoate agents, such as p-aminobenzoic acid (PABA), ethyl4-[bis(hydroxypropyl)] aminobenzoate, octyl dimethyl PABA, PABApropoxylate, glyceral PABA, 2-ethylhexyl PABA and pentyl PABA; cinnamateagents, such as cinoxate, diethanolamine-p-methoxy cinnamate,2-ethylhexyl-p-methoxycinnamate and octyl methoxycinnamate; benzones,such as oxybenzone, dioxybenzone, sulisobenzone; salicylates, such as2-ethylhexyl salicylate, triethanol amine salicylate, and octylsalicylate; and other sunscreen agents, such as titanium dioxide andzinc oxide. For use as a sunscreen, generally a thin gumresin/ultraviolet absorptive agent preparation is applied to areas ofthe skin that will be exposed to the sun. For some situations,protection of exposed skin from the sun will be best accomplished byapplying a thicker gum resin formulation, for example, for applicationof sunscreen to protect the skin of the nose at high altitudes.Advantageously, a gum resin/sunscreen compound formulation isparticularly effective at providing long-lasting sun protection toexposed skin through resisting removal by abrasion or moisture

[0033] Gum resin compositions may be prepared with pharmacologicalagents used for pigmenting or de-pigmenting the skin, for instance, foruse in treating patients with vitiligo. For treatments intending tode-pigment or lighten isolated dermal areas, a pharmacologic compositioncomprising hydroquinone (2%, 3%, 4%) is prepared. For treatmentsintending to pigment desired areas of skin, a composition comprising apsoralen agent, such as methoxalen (1.0%), for combined use with UVlight, is prepared.

[0034] A medicated dressing will also find use in the sustained deliveryof anti-perspirants, anti-anginal, anti-nausea agents and anti-canceragents. Particularly contemplated are compositions comprising aluminumchloride (20%), for the inhibition of perspiration of isolated dermalareas, for instance to aid in carrying out surgical procedures. A gumresin composition comprising nitroglycerin (0.5%, 1.0%, 2.0%) will finduse in the sustained transdermal delivery of this anti-anginal agentwhich can provide relief from chest pains. Relief from nausea, due tomotion sickness for example, can be provided using a biological dressingcomprising scopolamine. For anti-nausea purposes, a gumresin/scopolamine composition would be applied, behind the ear forexample, before the onset of activity that potentially would inducenausea. Additionally, a gum resin dressing can be prepared for thesustained delivery of pharmacological agents useful in the treatment ofsuperficial cancerous and pre-cancerous lesions. Particularlycontemplated is the treatment of isolated actinic keratosis lesions witha biological dressing comprising 5-fluorouracil (5-FU; 5%, 10%).

[0035] A gum resin carrier may also be prepared with an insect repellantas the pharmacologic agent. Examples of insect repellant compoundssuitable for inclusion in a biological dressing include terpenoids, suchas citronellal, geraniol, terpentine, pennyroyal, cedarwood, eucalyptusand wintergreen; benzoquinones; aromatics, such as cresols,benzaldehyde, cinnamic aldehyde, benzoic acids; and synthetic insectrepelling agents, such as N,N-diethyl-m-toluamide (DEET), ethylhexanediol, dimethyl phthalate, dimethyl ethyl hexanediol, carbate,butopyronoxyl, di-n-propyl isocinchonmeronate, N-octyl bicycloheptene,dicarboximide, and 2,3,4,5-bis(2-butylene)tetra-hydro-2-furaldehyde. Foruse as an insect repellent, a gum resin preparation is preferablyapplied as a thin coat to areas of the skin most likely to be attackedby an insect. Preferably, the insect repellant compound used repelsinsects without irritating the skin. Advantageously, as with thesunscreen preparations described above, a gum resin/insect repellentformulation is particularly effective at providing long-lasting insectrepellency on the skin through resisting removal by abrasion ormoisture.

[0036] Gum resin compositions also find use in the treatment of drugaddiction. Compositions containing nicotine, generally about in anamount sufficient to decrease nicotine addition, 14-22 mg perapplication, or other amounts as appropriate, find use in the reductionand/or cessation of cigarette smoking, chewing tobacco or other nicotinecontaining compounds. The compositions are applied to the skin in alocation that provides sufficient absorption of the nicotine, typicallythe upper arm. As the need for nicotine decreases the dosage of nicotinein the composition can be adjusted downward.

[0037] Optionally, the biologic dressing may include a penetrationenhancer, i.e., a chemical compound that, when included in aformulation, temporarily increases the permeability of the skin to adrug allowing more of the drug to be absorbed in a shorter period oftime. Examples of penetration enhancers that can be used includedimethylsulfoxide, n-decyl methyl sulfoxide, N,N-dimethylacetamide,N,N-methyl-2-pyrrolidone and octylphenylpolyethylene glycols.

[0038] The biologic dressing may also include other pharmaceuticallyacceptable carriers as needed that do not adversely affect theeffectiveness of the drug, or the resinous delivery vehicle and do notdamage the skin to which it is applied. Suitable pharmaceutical carriersinclude sterile water; saline, dextrose; dextrose in water or saline;condensation products of castor oil and ethylene oxide combining about30 to about 35 moles of ethylene oxide per mole of castor oil; liquidacid; lower alkanols; oils such as corn oil; peanut oil, sesame oil andthe like, with emulsifiers such as mono- or di-glyceride of a fattyacid, or a phosphatide, e.g., lecithin, and the like; glycols;polyalkylene glycols; aqueous media in the presence of a suspendingagent, for example, sodium carboxymethyl-cellulose; sodium alginate;poly(vinyl pyrrolidone); and the like, alone, or with suitabledispensing agents such as lecithin; polyoxyethylene stearate; and thelike. The carrier may also contain adjuvants such as preservingstabilizing, wetting, emulsifying agents and the like.

[0039] In practicing a method of treating the symptoms of adermatological disease in a patient, the pharmacological composition inits original prepared form, is applied directly and specifically on thelesions or other damaged areas of skin requiring treatment. Thebiological dressing composition may initially be prepared in any formsuitable for topical application, such as a paste, a liquid, asemi-solid, a gel, a suspension, an emulsion or the like, provided thatthe formulation allows the gum resin carrier and pharmacologicallyactive agent to effectively adhere together to the skin surface to whichthey are applied and to form a protective barrier over the skin once thevolatile solvent has evaporated. To minimize waste, application isgenerally carried out by painting or swabbing the composition at theaffected site or sites, but certain preparations can also be applied byspraying on the formulation, and allowing it to dry. The biologicdressing composition can be applied wherever the patient has superficialskin lesions or infections, such as on cutaneous areas, mucousmembranes, and mucocutaneous junctions (i.e., perianal, intertriginousand vulvovaginal areas). After application, the volatile solventevaporates to leave a protective solidified, adherent and hydrophobicfilm or coating on the skin surface to which it has been applied. Thesolidified film residue comprises the gum resin carrier, and thepharmacologically active agent or agents. By forming a barrier holdingthe pharmacologically active agent to the surface, the gum resin permitsa sustained, continuous release and a prolonged exposure to the agent oragents. Continuous exposure of the skin to the medication is maintainedas long as the coating stays in place. The biologic dressing, thereforecan effect symptomatic relief with less frequent applications. For mostdermatological disorders treated using a gum resin-based dressing, oneor two daily applications will be sufficient to promote regression ordisappearance of the targeted skin lesions. For certain less respondentlesions, three daily applications may be required to effectdisappearance of symptoms. Other dermatological disorders may requireapplication every second day to realize symptomatic relief. Thecomposition conveniently can be removed at will, by application of anappropriate solvent, normally ethanol. The composition can also beremoved by scrubbing with soap and water.

[0040] The invention now being generally described, it will be morereadily understood by reference to the following examples which areincluded for purposes of illustration only and are not intended to limitthe present invention.

EXAMPLES Example 1 Treatment of Athlete's Foot (Tinea pedis) with a GumResin-based Biological Dressing Comprised of Tinture of Benzoin andClotrimazole

[0041] Tincture of benzoin compositions are produced with standardtincture of benzoin (3M, Minneapolis, Minn.). Replicated experimentswere performed with a composition comprising tincture of benzoin with60% alcohol plus 1% clotrimazole. To determine efficacy in treatingathlete's foot, the benzoin/clotrimazole composition was applied tocases of athlete's foot, replicated 5 times. In each replicate, thecomposition led to complete clearance of the athlete's foot within 1week, when applied twice daily for 7 days. No allergic reaction wasnoted in this test, although the alcohol component reportedly led tostinging when applied to deep fissures. Minimal lint from the socks wasnoted on the coating where the composition was applied but was easilyremoved with ethanol. Efficacy of the benzoin/clotrimazole compositionwas compared to controls of tincture of benzoin alone and no treatment.The benzoin/clotrimazole composition provided symptomatic relief and ledto healing more quickly than tincture of benzoin alone, though tinctureof benzoin alone improved symptoms and signs more quickly when comparedto no treatment. This is likely due to the fact that the sticky coatingfrom the tincture tends to repel moisture. Efficacy of thebenzoin/clotrimazole composition also was compared to commerciallyavailable medications such as Lamisil®, Lotrimin®, Mycelex® andTinactin®. In comparison, the benzoin/clotrimazole composition greatlydecreased the time necessary for treatment compared to formulations ofeach of the commercial medications, particularly when the commercialmedications were administered in the form of powder, liquid, solution,spray or gel. The benzoin/clotrimazole composition also decreased thetime necessary for treatment when compared to cream versions of theabove medications and was much less messy than any of the commercialpreparations tested.

[0042] The above results demonstrate the improved symptomatic relieffrom a dermatological disorder that can be achieved by administering atopically acceptable pharmacological agent in a gum resin carrier thatforms a biological bandage in comparison presently available carriers.With a gum-resin-based biological dressing, relief from the unpleasantsymptoms associated with a dermatological lesion is realized moreefficiently and in a more convenient and palatable manner.

[0043] All publications and patent applications mentioned in thisspecification are indicative of the level of skill of those skilled inthe art to which this invention pertains. All publications and patentapplications are herein incorporated by reference to the same extent asif each individual publication or patent application was specificallyand individually indicated to be incorporate by reference.

[0044] The invention now having been fully described, it will beapparent to one of ordinary skill in the art that many changes andmodifications can be made thereto without departing from the spirit orscope of the appended claims.

What is claimed is:
 1. A pharmacological composition comprising: a) a gum resin; b) at least one topically acceptable pharmacologically active agent other than said gum resin that is effective as a treatment for ameliorating symptoms of a disease of skin or a mucous membrane of a mammal, wherein said pharmacologically active agent can remain in contact with said skin or said mucous membrane greater than 6 hours without toxic effects to said mammal; and c) a topically acceptable volatile solvent for said gum resin and said pharmacologically active agent.
 2. The composition according to claim 1, wherein said gum resin comprises benzoin.
 3. The composition according to claim 1, wherein said topically acceptable volatile solvent comprises ethanol.
 4. The composition according to claim 3, wherein said topically acceptable volatile solvent is ethanol and comprises about 60% to 90% of said composition.
 5. The composition according to claim 1 wherein said pharmacologically active agent is an antimicrobial agent.
 6. The composition according to claim 5 wherein said antimicrobial agent is an anti-fungal agent.
 7. The composition according to claim 6, wherein said anti-fungal agent is clotrimazole.
 8. The composition according to claim 7, wherein said clotrimazole is present as 1% of said composition.
 9. The composition according to claim 1 wherein said pharmacologically active agent is a steroidal agent.
 10. The composition according to claim 9, wherein said steroidal agent is betamethasone.
 11. The composition according to claim 10, wherein said betamethasone is present as 0.025-0.05% of the composition.
 12. The composition according to claim 1, wherein said pharmacologically active agent comprises both an antimicrobial agent and a steroidal agent.
 13. The composition according to claim 1, further comprising a penetration enhancer.
 14. A pharmacological composition comprising: a) a benzoin; b) clotrimazole; and c) ethanol.
 15. A method of increasing the effectiveness of a treatment for ameliorating the symptoms of a dermatological disease in a patient in need thereof, said method comprising: a) contacting sites on the skin of said patient exhibiting symptoms of said dermatological disease with a pharmacological composition according to claim 1; and b) allowing said composition to dry so that it forms a film on said skin, so that the effectiveness of said treatment for ameliorating said symptoms is increased.
 16. The method according to claim 15, wherein said dermatological disease is a fungal infection and said pharmacologically active agent is an anti-fungal compound.
 17. The method according to claim 16, wherein said fungal infection is athletes foot.
 18. The method according to claim 16 or 17, wherein said anti-fungal compound is clotrimazole at a concentration of about 1% by weight.
 19. The method according to claim 15, wherein said dermatological disease is an inflammatory disease of the skin.
 20. The method according to claim 19, wherein said inflammatory disease is selected from the group consisting of eczema, seborrheic dermatitis and psoriasis.
 21. The method according to claim 19 or 20, wherein said pharmacologically active agent is an anti-inflammatory steroidal agent.
 22. The method according to claim 21, wherein said anti-inflammatory steroidal agent is betamethasone at a concentration of about 0.025% to 0.05% by weight.
 23. The method according to claim 15, wherein said dermatological disease is a bacterial infection.
 24. The method according to claim 23, wherein said pharmacologically active agent is an anti-bacterial agent.
 25. A method of producing a biological dressing as a treatment for ameliorating symptoms of a disease of skin or a mucous membrane, said method comprising: drying a composition according to claim 1 on the skin or a mucosal membrane of a mammal at a site exhibiting symptoms of said disease so that it forms a film on said skin or mucosal membrane, whereby a biological dressing is obtained for ameliorating said symptoms.
 26. A biological dressing obtained according to the method of claim
 25. 27. A pharmacological composition comprising: a) a benzoin; b) 1% clotrimazole ; and c) 60% ethanol.
 28. A method of treating athlete's foot, said method comprising the steps of: a) contacting sites on the skin exhibiting symptoms of athlete's foot with a pharmacological composition according to claim 14 or 27; and b) allowing said composition to dry so that it forms a film on said skin, so that said symptoms of athlete's foot are treated. 